Assessment of antibody responses against gp41 in HIV-1-infected patients using soluble gp41 fusion proteins and peptides derived from M group consensus envelope

Penn-Nicholson, Adam; Han, Dong; Kim, Soon J.; Park, Hanna; Ansari, Rais A.; Montefiori, David C.; Cho, Michael W.

doi:10.1016/j.virol.2007.11.009

Cited by 19 publications

(20 citation statements)

References 89 publications

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“…Although several studies discussed the presence of binding anti-MPER antibodies in HIV ϩ plasmas (12,24,26), there has not been a report on the presence of antibodies that recognize the 4E10 epitope and that possess neutralizing activities. In fact, it was proposed that due to the cross-reactivity of MAb 4E10 with self antigens, such as certain membrane lipids, B cells that secrete 4E10-like antibodies are eliminated during B-cell differentiation (13).…”

Section: Discussionmentioning

confidence: 99%

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Sather

Armann

Ching

et al. 2009

J Virol

485

347

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The characterization of the cross-reactive, or heterologous, neutralizing antibody responses developed during human immunodeficiency virus type 1 (HIV-1) infection and the identification of factors associated with their generation are relevant to the development of an HIV vaccine. We report that in healthy HIV-positive, antiretroviral-naïve subjects, the breadth of plasma heterologous neutralizing antibody responses correlates with the time since infection, plasma viremia levels, and the binding avidity of anti-Env antibodies. Anti-CD4-binding site antibodies are responsible for the exceptionally broad cross-neutralizing antibody responses recorded only in rare plasma samples. However, in most cases examined, antibodies to the variable regions and to the CD4-binding site of Env modestly contributed in defining the overall breadth of these responses. Plasmas with broad cross-neutralizing antibody responses were identified that targeted the gp120 subunit, but their precise epitopes mapped outside the variable regions and the CD4-binding site. Finally, although several plasmas were identified with cross-neutralizing antibody responses that were not directed against gp120, only one plasma with a moderate breadth of heterologous neutralizing antibody responses contained cross-reactive neutralizing antibodies against the 4E10 epitope, which is within the gp41 transmembrane subunit. Overall, our study indicates that more than one pathway leads to the development of broad cross-reactive neutralizing antibodies during HIV infection and that the virus continuously escapes their action.

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Section: Discussionmentioning

confidence: 99%

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Sather

Armann

Ching

et al. 2009

J Virol

485

347

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“…The orientation was identified by PCR, and the sequence was confirmed by sequencing. Protein expression and purification was performed according to the method of Penn-Nicholson et al (24) with slight modifications. For gp41-HR1-54Q expression, Escherchia coli T7 Express IysY/I q (New England Biolabs) was transformed with pET-gp41-HR1-54Q and cultured overnight at 37°C in superbroth containing ampicillin (50 g/ml).…”

Section: Methodsmentioning

confidence: 99%

Structural Characterization of HIV gp41 with the Membrane-proximal External Region

Shi

Bohon

Han

et al. 2010

Journal of Biological Chemistry

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Human immunodeficiency virus, type 1 (HIV-1) envelope glycoprotein (gp120/gp41) plays a critical role in virus infection and pathogenesis. Three of the six monoclonal antibodies considered to have broadly neutralizing activities (2F5, 4E10, and Z13e1) bind to the membrane-proximal external region (MPER) of gp41. This makes the MPER a desirable template for developing immunogens that can elicit antibodies with properties similar to these monoclonal antibodies, with a long term goal of developing antigens that could serve as novel HIV vaccines. In order to provide a structural basis for rational antigen design, an MPER construct, HR1-54Q, was generated for x-ray crystallographic and x-ray footprinting studies to provide both high resolution atomic coordinates and verification of the solution state of the antigen, respectively. The crystal structure of HR1-54Q reveals a trimeric, coiled-coil six-helical bundle, which probably represents a postfusion form of gp41. The MPER portion extends from HR2 in continuation of a slightly bent long helix and is relatively flexible. The structures observed for the 2F5 and 4E10 epitopes agree well with existing structural data, and enzyme-linked immunosorbent assays indicate that the antigen binds well to antibodies that recognize the above epitopes. Hydroxyl radical-mediated protein footprinting of the antigen in solution reveals specifically protected and accessible regions consistent with the predictions based on the trimeric structure from the crystallographic data. Overall, the HR1-54Q antigen, as characterized by crystallography and footprinting, represents a postfusion, trimeric form of HIV gp41, and its structure provides a rational basis for gp41 antigen design suitable for HIV vaccine development.The HIV 2 glycoprotein is initially expressed as the precursor protein gp160, which is post-translationally cleaved into two non-covalently associated proteins: gp120, the receptor-binding protein that targets the CD4 receptor, and gp41, which mediates the fusion of the viral and host cellular membranes (1, 2). The native, prefusion form of the gp120-gp41 complex is thought to be a trimer comprising three gp120 subunits and three membrane-anchored gp41 subunits and is in a metastable conformation with the heavily glycosylated gp120 shielding gp41 (3, 4). Upon binding of gp120 to CD4 and a co-receptor (CCR5 or CXCR4), gp41 undergoes a large conformational change to form the prehairpin fusion intermediate in which the N-terminal and C-terminal helices separate from each other and the fusion peptide extends toward the host membrane (1, 5). This ultimately leads to the fusion of the viral and host membranes and leaves a postfusion form of gp41 with a structure of hairpins in a trimer.Several crystal structures of HIV-1 and simian immunodeficiency virus gp41 have been reported (6 -9). All structures contain the gp41 core, which is composed of the two heptad repeat regions, the N-terminal helical heptad repeat (HR1) and the C-terminal helical heptad repeat (HR2). The largest structur...

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“…Mut(e,g) may potentially be able to enhance the anti-HIV potency of the gp41-directed immune response by converting some of the nonneutralizing or very weakly neutralizing N-HR gp41-directed Abs found in patient sera (39) to neutralizing Abs and may also represent a potentially useful adjunct in treatment of AIDS with gp41-directed neutralizing MAbs. Table 3.…”

Section: Synergistic Neutralization Of Primary Hiv-1 Isolates By Bf-3mentioning

confidence: 99%

Sequestering of the Prehairpin Intermediate of gp41 by Peptide N36 ^Mut(e,g) Potentiates the Human Immunodeficiency Virus Type 1 Neutralizing Activity of Monoclonal Antibodies Directed against the N-Terminal Helical Repeat of gp41

Gustchina

Bewley

Clore

2008

J Virol

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Assessment of antibody responses against gp41 in HIV-1-infected patients using soluble gp41 fusion proteins and peptides derived from M group consensus envelope

Cited by 19 publications

References 89 publications

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Structural Characterization of HIV gp41 with the Membrane-proximal External Region

Sequestering of the Prehairpin Intermediate of gp41 by Peptide N36 ^Mut(e,g) Potentiates the Human Immunodeficiency Virus Type 1 Neutralizing Activity of Monoclonal Antibodies Directed against the N-Terminal Helical Repeat of gp41

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Assessment of antibody responses against gp41 in HIV-1-infected patients using soluble gp41 fusion proteins and peptides derived from M group consensus envelope

Cited by 19 publications

References 89 publications

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Structural Characterization of HIV gp41 with the Membrane-proximal External Region

Sequestering of the Prehairpin Intermediate of gp41 by Peptide N36 Mut(e,g) Potentiates the Human Immunodeficiency Virus Type 1 Neutralizing Activity of Monoclonal Antibodies Directed against the N-Terminal Helical Repeat of gp41

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Sequestering of the Prehairpin Intermediate of gp41 by Peptide N36 ^Mut(e,g) Potentiates the Human Immunodeficiency Virus Type 1 Neutralizing Activity of Monoclonal Antibodies Directed against the N-Terminal Helical Repeat of gp41